Within the scope of current medical care and especially in the Intensive Care Unit (ICU), concern for inter-drug compatibility has always been a matter of life-and-death proportion. The compatibility of chemicals, especially drugs, with one another in solution generally includes many factors such as physical compatibility of the chemicals and the diluent employed, chemical stability, chemical interactions and absorption issues. Indications of physical incompatibility include the formation of haze, turbidity, precipitate, crystals and globules. The present invention relates to physical compatibility.
Intravenous drug and solution compatibility testing, at least from the standpoint of physical compatibility, began over 30 years ago. In 1955, R. Bogash published an article, "Compatibilities and Incompatibilities in Some Parenteral Medications" in a bulletin from the American Society of Hospital Pharmacists (12:455-488, July-Aug., 1955). Since then, there has been a substantial body of literature on the subject of intravenous compatibility. One of the largest studies ever performed was published by Kirkland, et al, entitled, Compatibility Studies of Parenterals Admixtures, in the American Journal of Hospital Pharmacy (18:694-699, Dec, 1961). It reported physical compatibility results for about 4,000 combinations of 68 drug combinations diluted in 59 infusion solutions. To date, this is the largest study published on physical compatibility results.
Another major study by Patel and Phillips (Am. J. Hosp. Pharm., 23:409-411, 1966) reported results on about 3,000 drug combinations. In addition to these major studies, there are over 1,000 other articles on drug compatibility published to date.
Generally speaking, the more serious a patient's condition, the more drugs the patient will be receiving. The average number of drugs per patient administered in a typical ICU is 10-12 per day. These drugs usually are administered at 2-4 delivery doses per day, for a total of 20-48 drug doses per day. This number is exclusive of other required fluids and nutritional solutions. It is not uncommon for patients to receive 50-70 drug doses per day and there have been specific cases where patients have received over 100 drug doses per day. The phenomena of such critically ill patients taking such a large number of medication doses per day has created acceptance of the practice termed "polypharmacy".
These large numbers of drug doses create an increased risk of medication errors, the consequences of which are often totally unforeseen. In treating a critically ill patient the clinician must assume that the drugs can be, and are in fact administered at the prescribed times, and at the prescribed infusion rates and that the drugs are compatible with one another. In the past, clinicians have generally assumed that the mixing within an intravenous line is minimal and that back-to-back solutions administered sequentially through the same intravenous line move through the line with a minimal interface, and therefore little if any reaction, between them.
Recent studies have shown that this is an incorrect assumption. There is substantial mixing as two fluids pass down an intravenous line, even sequentially. This mixing raises important issues on potential clinical problems in drug administration and drug-drug compatibilities in the practice of polypharmacy. In cases where no compatibility information is available, additional intravenous catheters are generally placed in the patient through which additional drugs are delivered, thus increasing the risks for contamination and sepsis in these already compromised patients. Alternatively, the risk is taken that the drugs are compatible and they are infused continuously, or sequentially down the same line.
The issues of multiple intravenous lines, contamination of lines and medication errors have created the need for automation to meet the increasing demand to administer these multiple drug doses. All of this only serves to further highlight the substantial need for vastly expanded information relating to physical compatibility and fluid mixing to enable clinicians to correctly and safely prescribe and administer the multiple doses of multiple drugs. Until all of these needs are met, the quality of care to patients is reduced, compromised and even at times inadequate and life threatening.
Currently in medical practice, there are about 300 unique drugs available for intravenous administration to patients. This number rapidly increases if one includes the various manufacturers' formulations for each drug and the various solutions and diluents available. When assessing compatibilities during the short-term mixing that occurs during intravenous drug administration, the focus is primarily on physical compatibility as related to solubility and/or precipitates because of the potentially devastating effects of intravenous particles.
From the fact that there are about 300 unique drugs currently available, one can readily calculate that, if one limits his concern to combinations of two drugs only, there are about 45,000 unique combinations for which physical compatibility data is necessary to complete the dataset for a given diluent such as 0.9% saline. Furthermore, the order of addition of multiple drugs to a solution can effect the result and therefore each combination of drugs must be tested in all possible orders of addition. This consideration brings to about 90,000 the number of physical compatibility tests necessary to complete an entire matrix of data for a given diluent when testing all possible two drug combinations of the 300 unique drugs to be considered. As can be appreciated, when combinations of three or more drugs are considered, this number increases exponentially. Similarly, the number goes up dramatically when one takes into account the various manufacturers' formulations for each given drug. One might also be legitimately concerned with the various dosages available for each drug.
Additionally, there are two major diluents for intravenous drugs, 5% dextrose in water and 0.9% saline in water, and for completeness, each combination should be evaluated in a mixture of these two major diluents and at least a 50/50 combination of the two. Our number therefore grows to about 270,000 drug-drug physical compatibility tests which are required, still limiting ourselves to only two-drug combinations, to complete the dataset matrix to supply the modern physician with a complete and relevant database from which multiple intravenous medications can be safely and effectively prescribed and administered.
The reference book, Handbook on Injectable Drugs, by Lawrence Trissel, is a compilation of all compatibility information published over the last 30 years. It has over 700 pages, summarizes essentially all of the published data on inter-drug compatibility and is the most cited reference source for drug and solution compatibility information. The Handbook contains the results of about 15,000 compatibility tests, the fruits of over thirty years of work. Therefore, over the last thirty years, less than 10% (15,000) of the possible combinations have been tested and reported. The amount of necessary information that is missing from the published literature available to the medical profession is staggering.
Not only is the published state of the art sorely incomplete, but the methodology used to generate the results in the published literature is not standardized (not a USP test), is totally subjective (visual observations) and performed manually. Additionally, some of this testing is out of date or not applicable to today's advanced infusion techniques. For example, a current focus is on Y-site injection of drugs rather than premixing in a reservoir, a technique not considered in the prior art methods of gathering inter-drug compatibility data.
There are other issues which must also be considered if the data upon which the physician relies is to be trustworthy. These include such considerations as whether the drug was tested at too dilute a concentration for the proposed application or for non-relevant time period(s) and under conditions not relevant to those under which the drug would generally be administered. For example, such data has traditionally been collected by the prior art manual and subjective means after the drugs had been in contact with each other for at least 24 hours and in whatever container and/or quantities the researchers chose, which were often quite arbitrary. However, in current intravenous practice, unless intentionally so, particular quanta of two drugs are rarely if ever in contact with each other for more than a matter of minutes, and then in very small quantities within the lumen of the IV tube.
In 1987-88, Dasta et al. began to reassess the issue of drug compatibility (Dasta, et al., Comparison of Visual and Turbidimetric Methods for Determining Short-Term Compatibility of Intravenous Critical-Care Drugs, American Journal of Hospital Pharmacy, vol. 45, pp 2361-2366, Nov. 1988). The stated motivation for the study was the fact that the current literature on compatibilities is largely based on studies that used methodologies that do not apply to the ICU environment. It was recognized that rarely is there any information that is specifically applicable to this situation. In an attempt to standardize and semi-automate the laborious procedures historically employed, he designed a study to re-evaluate the short-term compatibility of 45 previously considered "incompatible" drug-drug combinations under more relevant conditions and to compare the historical, non-standardized visual observations with the absorbance changes due to turbidity as recorded by a spectrophotometer. He found that about 50% of the previously listed "physically incompatible" combinations, were in fact compatible when tested under conditions relevant to the ICU. Additionally and interestingly, the turbidity measurement using spectrophotometry was not reliable as it was unable to consistently detect changes that were observed visually. The author concludes that detection may require a more sophisticated instrument and that perhaps other techniques could be developed to overcome the inadequacies of this system. Given that there was no alternative automated process adapted to ascertain physical compatibility of drugs, it was estimated that even with his ability to speed-up the subjective, laborious, visual test system of the prior art, it would take a group about 41 years to complete the database of relevant information on physical drug compatibility in two solution vehicles.
Since that time, a number of automated test systems for various applications other than physical compatibility of drugs have been developed. One such alternative automated detection method is disclosed in U.K. Pat. No. 2,030,696. The essence of this disclosure is a semiquantitative mathematical algorithm for detecting the appearance or disappearance of color or turbidity using serial dilutions examined over an absorbance range. Another detection method is disclosed in Research Disclosure *17543 (November, 1978), which includes modifying a spectrophotometer to measure haze in beverage bottles. The system does not detect precipitation.
Another device and method is disclosed in W086/07454. This publication discloses a particular apparatus for determining color and turbidity in which light collected after traversing a sample is chromatically dispersed and the intensity of each of the components of the dispersion is measured. The apparatus and method disclosed are used for the control of transportation of liquid oil through pipelines.
U.S. Pat. No. 4,108,602 discloses an automated sample changing system for chemical analysis. It transports the samples to and from an analysis apparatus, such as a UV spectrophotometer. U.S. Pat No. 4,678,326 discloses an apparatus for measuring various optical properties of a liquid sample. U.S. Pat. No. 4,497,898 discloses a method for detecting both the protein and fat content of milk simultaneously, which method employs, inter alia, color developing reagents and simultaneous multiple single source light beams. However, the method disclosed in this reference is incapable of detecting precipitation. U.S. Pat. No. 4,429,373 describes a system for the spectrophotometric analysis of blood for its constituents.